Metabolic activation of 25-hydroxyvitamin D3 (25-OHD3) to 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) occurs in the kidney and is under endogenous control. This study is directed toward identifying the modulatory system and explaining the associated molecular processes. Parathyroid hormone (PTH) and calcitonin (CT) are being evaluated as possible mediators between the disturbing signal and resultant change in kidney hydroxylase enzyme activity. Cellular mechanisms for the control of kidney 25-OHD3 metabolism are being studied in light of intracellular factors which could effect modification of the mitochondrial 25-OHD3 hydroxylase enzymes. Cations (calcium, strontium, magnesium), phosphate, cyclic AMP, and prostaglandins are being evaluated in the control process. The molecular mechanism is also being studied with respect to possible suppression and derepression mechanisms and the requirement for de novo enzyme synthesis.